Hydroxyalkyl cyclic diamine compound

ABSTRACT

The present invention is directed to a compound represented by the following formula (1) and to a process for producing a compound (5) from the compound (1). 
     
       
         
         
             
             
         
       
     
     By use of the compound (1) of the present invention, a variety of cyclic diamine derivatives (5) or salts thereof, useful as drugs, can be produced in an industrially advantageous manner with a constant yield.

TECHNICAL FIELD

The present invention relates to novel hydroxyalkyl cyclic diaminecompounds, and to a process for preparing cyclic diamine derivatives andsalts thereof.

BACKGROUND ART

Acyl coenzyme A cholesterol acyltransferase (ACAT) is an enzyme servingfor catalyzing the synthesis of cholesteryl ester from cholesterol,playing an important role in the metabolism of cholesterol and intake ofcholesterol in the digestive organs.

In recent years, it has been clarified that when the activity of ACATpresent in the small intestine or the liver is suppressed, elevation ofblood cholesterol can be effectively prevented, and a number of studieshave heretofore been undertaken regarding ACAT inhibitors.

The present inventors focused on ACAT in vascular wall and studied onthe selective inhibitors against this type of ACAT, thus leading to thefinding that azole compounds having a cyclic diamine structure,particularly cyclic diamine derivatives of formula (5′):

(wherein A denotes NH, an oxygen atom or a sulfur atom, W^(a) to W^(d)denote CH or any one of the W^(a) to W^(d) denotes a nitrogen atom,R^(a) denotes a lower alkylthio group, a lower alkoxy or halo-loweralkoxy group, a lower alkoxy lower alkoxy group, each of R^(b), R^(c),and R^(d) denotes a hydrogen atom, a halogen atom, a lower alkyl group,a lower alkoxy group, a lower alkoxy carbonyl group, a halo-lower alkylgroup, a halo-lower alkoxy group, a lower alkoxy lower alkyl group, alower alkoxy lower alkoxy group, a hydroxy lower alkyl group, a hydroxylower alkoxy group, a lower alkylcarbonyl group, a lower alkylthiogroup, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a nitrogroup, or a cyano group, m is 1 or 2, and n is an integer of 1 to 6) orsalts thereof exhibit reduced side effects, high water-solubility, andexcellent oral absorption property and thus are useful as a remedy forhyperlipidemia and arteriosclerosis. As a result, the present inventorsfiled a PCT patent application (see WO98/54153 pamphlet).

That patent application discloses a process for preparing cyclic diaminederivatives (5′) through the below-described production process 1(Example 24) or the below-described production process 2 (Example 88).However, there have still been problems in such processes. For example,the following problems are noted: 1) production process 1 requires manysteps because of protection and deprotection for an amino group of apiperazine ring; 2) production process 1, and production process 2 whichdoes not use the protective group, have difficulty of synthesizing acyclic diamine derivative (5′) in which the substituent (R^(a)) on thepyridine ring is mono- or di-lower alkyl amino group or a cyclic aminogroup; and 3) the chlorine atoms in compound (7b) are so highly reactivethat the compound substituted by a methoxy group at the 4-positionthereof is undesirably produced as a by-product in the reaction processperformed in methanol for introducing a lower alkylthio group,and itsremoval is extremely difficult.

DISCLOSURE OF THE INVENTION

Objects of the present invention include a production intermediatecapable of industrially and advantageously synthesizing a cyclic diaminederivative (5), serving as an ACAT inhibitor, or a salt thereof; aprocess for preparing a cyclic diamine derivative (5) or a salt thereof.

Under the above circumstance, the present inventors have carried outextensive research, and found that, as shown in the below-describedreaction scheme, a process which passes a novel hydroxyalkyl cyclicdiamine compound (1) which can be obtained from3-amino-2,4-dihalogeno-6-methylpyridine (7) serving as a startingmaterial, can successfully produce any relevant compound having, as aside chain of the pyridine ring, a mono- or di-lower alkyl amino groupor a cyclic amino group, and that a variety of cyclic diaminederivatives (5) or their salts can be produced at a high yield with highpurity.

(wherein A denotes NH, an oxygen atom or a sulfur atom, each of W¹ to W⁴denotes CH or any one of the W¹ to W⁴ denotes a nitrogen atom while theother three of W¹ to W⁴ denote CH, R¹ denotes a halogen atom, R² denotesa lower alkylthio group, a mono- or di-lower alkylamino group, a cyclicamino group, a lower alkoxy group, a halo-lower alkoxy group, or a loweralkoxy lower alkoxy group, each of R³, R⁴, and R⁵ denotes a hydrogenatom, a halogen atom, a lower alkyl group, a lower alkoxy group, a loweralkoxycarbonyl group, a halo-lower alkyl group, a halo-lower alkoxygroup, a lower alkoxy lower alkyl group, a lower alkoxy lower alkoxygroup, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, alower alkylcarbonyl group, a lower alkylthio group, a loweralkylsulfinyl group, a lower alkylsulfonyl group, a nitro group, or acyano group, R⁶ and R⁷, which may be identical to or different from eachother, independently denote a halogen atom, X denotes a leaving group, mis 1 or 2, and n is an integer of 1 to 6).

Accordingly, the present invention provides a hydroxyalkyl cyclicdiamine compound of formula (1).

The present invention also provides a process for producing a cyclicdiamine derivative of formula (5) or a salt thereof, characterized inthat the process comprises reacting a hydroxyalkyl cyclic diaminecompound of formula (1) with R²H to thereby form a compound of formula(2), transforming the hydroxyl group of the compound of formula (2) intoa leaving group to thereby form a compound of formula (3) and allowingthe compound (3) to react with a thiol derivative of formula (4), oralternatively allowing the compound (2) to react with a thiol derivativeof formula (4) or (4′) in the presence of a phosphorus compound.

The present invention also provides an acetamide compound of formula (6)and 3-amino-2,4-dibromo-6-methylpyridine of formula (7a), whichcorresponds to a compound of formula (7) wherein R¹ is a bromine atom.

The present invention also provides 2,4-dibromo-6-methyl-3-nitropyridineof formula (24) which is a starting material for producing a compound(7a).

The hydroxyalkyl cyclic diamine compounds of formula (1) according tothe present invention are useful intermediates for producing a varietyof pharmaceutically useful cyclic diamine derivatives (5) and theirsalts, and through use of such intermediates, the derivatives can beproduced in an industrially advantageous manner with a constant yield.

BEST MODE FOR CARRYING OUT THE INVENTION

Examples of the halogen atom represented by R¹, R⁶, or R⁷ in theformulae shown in the present specification include a chlorine atom, abromine atom, and an iodine atom. Of these, a chlorine atom and abromine atom are preferred.

In the formulae, m is 1 or 2, and n is an integer of 1 to 6. Preferably,m is 1, and n is 2 or 3.

Examples of the lower alkyl groups and the lower alkyl moieties of thelower alkoxy groups represented by R², R³, R⁴, or R⁵ include C1 to C6alkyl groups which are linear, branched, or cyclic.

Examples of the lower alkylthio groups represented by R² include amethylthio group, an ethylthio group, a n-propylthio group, anisopropylthio group, a cyclopropylthio group, a cyclopropylmethylthiogroup, a n-butylthio group and a cyclohexylthio group. Examples of themono- or di-lower-alkylamino groups represented by R² include amethylamino group, an ethylamino group, a n-propylamino group, anisopropylamino group, a cyclopropylamino group, a dimethylamino group, adiethylamino group, a di(n-propyl)amino group, a di(isopropyl)aminogroup and a di(cyclopropyl)amino group. Examples of the cyclic aminogroups represented by R² include a morpholino group, a piperidino groupand a pyrrolidinyl group. Examples of the lower alkoxy groupsrepresented by R² include a methoxy group, an ethoxy group, a n-propoxygroup, an isopropoxy group, a n-butoxy group, a cyclopropylmethyloxygroup, a cyclopropyloxy group, a cyclohexyloxy group, a cyclopentyloxygroup and a cyclobutyloxy group. Examples of the halo-lower alkoxygroups represented by R² include a difluoromethoxy group, atrifluoromethoxy group and a 2,2,2-trifluoroethoxy group. Examples ofthe lower alkloxy lower alkoxy groups represented by R² include amethoxyethoxy group, an ethoxymethoxy group and an ethoxyethoxy group.

Examples of the halogen atoms represented by R³, R⁴, or R⁵ include afluorine atom, a chlorine atom, and a bromine atom. Examples of thelower alkyl groups represented by R³, R⁴, or R⁵ include a methyl group,an ethyl group, a n-proypl group, a tert-butyl group and an isopropylgroup. Examples of the lower alkoxy groups represented by R³, R⁴, or R⁵include the same groups as mentioned in relation to R². Examples of thelower alkoxycarbonyl groups represented by R³, R⁴, or R⁵ include amethoxycarbonyl group, an ethoxycarbonyl group, a n-propoxycarbonylgroup and a tert-butoxycarbonyl group. Examples of the halo-lower alkylgroups represented by R³, R⁴, or R⁵ include a trifluoromethyl group anda 2,2,2-trifluoroethyl group. Examples of the halo-lower alkoxy groupsrepresented by R³, R⁴, or R⁵ include the same groups as mentioned inrelation to R². Examples of the lower alkoxy lower alkyl groupsrepresented by R³, R⁴, or R⁵ include a methoxymethyl group, anethoxymethyl group and a methoxyethyl group. Examples of the loweralkoxy lower alkoxy groups represented by R³, R⁴, or R⁵ include amethoxymethoxy group, an ethoxymethoxy group, a methoxyethoxy group andan ethoxyethoxy group. Examples of the lower hydroxyalkyl groupsrepresented by R³, R⁴, or R⁵ include a hydroxymethyl group, a2-hydroxyethyl group, a 2-hydroxy-2,2-dimethylethyl group and a3-hydroxy(n-propyl) group. Examples of the lower hydroxy-alkoxy groupsrepresented by R³, R⁴, or R⁵ include a 2-hydroxyethoxy group and a3-hydroxy(n-propoxy) group. Examples of the lower alkylcarbonyl groupsrepresented by R³, R⁴, or R⁵ include an acetyl group, a propionyl groupand a butyryl group. Examples of the lower alkylthio groups representedby R³, R⁴, or R⁵ include a methylthio group, an ethylthio group, an-propylthio group and an isopropylthio group. Examples of the loweralkylsulfinyl groups represented by R³, R⁴, or R⁵ include amethylsulfinyl group, an ethylsulfinyl group, a n-propylsulfinyl groupand an isopropylsulfinyl group. Examples of the lower alkylsulfonylgroups represented by R³, R⁴, or R⁵ include a methylsulfonyl group, anethylsulfonyl group, an n-propylsulfonyl group and an isopropylsulfonylgroup.

According to the present invention, the cyclic diamine derivative (5) ora salt thereof can be produced from the compound (1) via two or threesteps. The individual production steps will next be described.

[Step-1]

The intended compound (2) can be produced by transforming the halogenatoms of a hydroxyalkyl cyclic diamine compound (1) into desiredsubstituents.

(A) Synthesis of Thioether Compound (R²: a Lower Alkylthio Group)

The thioether compound can be synthesized by adding sodium loweralkylthioalkoxide powder or an organic solvent solution thereof, or anaqueous solution thereof to a solution containing the compound (1) and18-crown-6.

The sodium lower alkylthioalkoxide is preferably used in an amount of2.5 to 20 equivalents based on the amount of the compound (1), and18-crown-6 is preferably used in an amount of 0.05 to 0.5 equivalentsbased on the amount of the compound (1).

Examples of the solvent include diisopropy alcohol, dimethyl sulfoxide,N,N-dimethylformamide, N-methylpyrrolidone, and toluene. Of these,dimethyl sulfoxide is particularly preferred.

The reaction is preferably performed at a temperature within a range ofroom temperature to 150° C., more preferably 50 to 110° C. The reactiontime is preferably one hour to one day.

(B) Synthesis of Amino Compound (R²: a Mono- or Di-lower-alkylaminoGroup, or a Cyclic Amino Group)

The amino compound can be synthesized by adding an amine reagent; i.e.,a mono- or di-lower-alkylamine or a cyclic amine to a solution of thecompound (1).

The mono- or di-lower-alkylamine or cyclic amine is preferably used inan amount of 5 to 20 equivalents based on the amount of the compound(1).

Examples of the solvent include tetrahydrofuran, toluene, dimethylsulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone. The aminereagent can also be employed as the solvent.

The reaction is preferably performed at a temperature within a range ofroom temperature to 150° C., more preferably 50 to 110° C. The reactiontime is preferably 5 hours to 2 days. If necessary, the reaction may beperformed in a sealed tube.

(C) Synthesis of Ether Compound (R²: a Lower Alkoxy Group, a Halo-lowerAlkoxy Group, or a Lower Alkoxy Lower Alkoxy Group)

The ether compound can be synthesized by adding a solution of sodiumlower alkoxide, or sodium halo-lower alkloxide, or sodium lower alkoxylower alkoxide to a solution containing the compound (1) and 18-crown-6.

The sodium lower alkoxide, or sodium halo-lower alkloxide, or sodiumlower alkoxy lower alkoxide is preferably used in an amount of 2.5 to 20equivalents based on the amount of the compound (1), and 18-crown-6 ispreferably used in an amount of 0.05 to 0.5 equivalents based on theamount of the compound (1).

Examples of the solvent include tetrahydrofuran, toluene, dimethylsulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone. Of these,dimethyl sulfoxide is particularly preferred.

The reaction is preferably performed at a temperature within a range ofroom temperature to 150° C., more preferably 50 to 110° C. The reactiontime is preferably one hour to two days.

From the thus-produced compound (2), the compound (5) can be producedthrough, for example, either of the following routes: transforming thehydroxyl group of the compound (2) into a leaving group, to thereby formthe compound (3), followed by substitution reaction with a thiolderivative (4) (Steps 2 and 3); or reacting the compound (2) with athiol derivative (4) or (4′) using a phosphorus compound (Step 4).

[Step-2]

The compound (3) can be produced by reacting the compound (2) with areagent which allows transformation from the hydroxyl group into aleaving group; e.g., a sulfonylation agent or a halogenation agent.

No particular limtiation is imposed on the type of the leaving groupsrepresented by X so long as the groups can be readily transformed from ahydroxyl group and can be readily substituted by the thiol derivative(4). Examples of the leaving groups include sulfonyloxy groups such as amethanesulfonyloxy group, a chloromethanesulfonyloxy group, anethanesulfonyloxy group, a propanesulfonyloxy group, abenzenesulfonyloxy group, and a p-toluenesulfonyloxy group; and halogenatoms such as a chlorine atom, a bromine atom, and an iodine atom. Ofthese, a methanesulfonyloxy group is particularly preferred.

Transformation to a sulfonyloxy group is preferably performed bydissolving the compound (2) in a solvent, adding a sulfonylation agentto the solution, and leading to the reaction for 0.5 to 10 hours in thepresence or absence of a base, preferably at 0 to 60° C., morepreferably at 0° C. to room temperature.

Examples of preferred sulfonylation agents include methanesulfonylchloride, methanesulfonic anhydride, benzenesulfonyl chloride, andp-toluenesulfonyl chloride.

Examples of the base include organic bases such as triethylamine,4-dimethylaminopyridine, N,N-diisopropylethylamine, and pyridine; alkalimetal carbonates such as potassium carbonate and sodium carbonate; andalkali metal hydrogencarbonates such as potassium hydrogencarbonate andsodium hydrogencarbonate.

As a solvent, there may be employed tetrahydrofuran, acetonitrile,N,N-dimethylformamide, ethyl acetate, methylene chloride, chloroform,toluene, or dimethyl sulfoxide.

Transformation to a halogen atom is preferably performed by dissolvingthe compound (2) in a solvent, adding a halogenation agent to thesolution, and leading to the reaction for 0.5 to 10 hours in thepresence or absence of a base, preferably at 0 to 100° C., morepreferably at 0° C. to 60° C.

Examples of the halogenation agents include chlorination agents andbromination agents; e.g., phosphorus oxychloride, phosphoruspentachloride, dichlorotriphenylphosphine, dibromotriphenylphosphine,dichlorotriphenyl phosphite, dibromotriphenyl phosphite, phosphorustribromide, thionyl chloride, triphenylphosphine and carbontetrachloride, triphenylphosphine and carbon tetrabromide, andmethanesulfonyl chloride and 4-dimethylaminopyridine.

Examples of the solvents which may be used include dichloromethane,chloroform, benzene, toluene, tetrahydrofuran, pyridine, andN,N-dimethylformamide.

[Step-3]

The cyclic diamine derivative (5) can be produced by reacting, in asolvent, the compound (3) with a thiol derivative (4) in the presence orabsence of a base and a catalyst.

Examples of the base which may be used include organic bases such astriethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, andpyridine; alkali metal carbonates such as potassium carbonate and sodiumcarbonate; and alkali metal hydrogencarbonates such as potassiumhydrogencarbonate and sodium hydrogencarbonate. Examples of the catalystinclude crown ethers such as 18-crown-6 and 15-crown-5; and quaternaryammonium salts such as tetrabutylammonium chloride, tetrabutylammoniumbromide, tetrabutylammonium iodide, tetrabutylammonium hydrogensulfate,and benzyltrimethylammonium bromide. Of these, 18-crown-6 is preferred.

Examples of the solvents which may be used include tetrahydrofuran,acetone, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide.The reaction is generally performed at 0 to 120° C., preferably at 20 to100° C. for 0.5 to 10 hours, preferably for 1 to 3 hours.

[Step-4]

Examples of the phosphorus compound employed in Step-4 include phosphinereagents used in Mitsunobu reaction; combined phosphorus reagentscontaining one of the phosphine reagents and an azo reagent or anethylenedicarboxylic acid reagent such as dimethyl maleate orN,N,N′,N′-tetramethylfumaramide; and phosphonium ylide reagents.

Preferred modes for carrying out Step-4 include (1) reacting thecompound (2) with a thiol derivative (4) in the presence of a phosphinereagent and an azo reagent or an ethylenedicarboxylic acid reagent suchas dimethyl maleate or N,N,N′,N′-tetramethylfumaramide (Method A); (2)reacting the compound (2) with a thiol derivative (4) in the presence ofa phosphonium ylide reagent (Method B); (3) reacting the compound (2)with a thiol derivative (4′) in the presence of a phosphine reagent(Method C).

<Method A>

Method A can be carried out by dissolving the compound (2), a thiolderivative (4), and a phosphine reagent in a reaction solvent, adding anazo reagent or an ethylenedicarboxylic acid reagent to the solution, andleading to the reaction under argon or nitrogen atmosphere for 2 hoursto one day at 0° C. to 100° C., preferably between room temperature and80° C.

Examples of the phosphine reagent employed in the reaction includetrialkylphosphines such as trimethylphosphine, triethylphosphine,tripropylphosphine, triisopropylphosphine, tributylphosphine,triisobutylphosphine, and tricyclohexylphosphine; and triarylphosphinesuch as triphenylphosphine and diphenylphosphinopolystyrene. Of these,trimethylphosphine, tributylphosphine, and triphenylphosphine arepreferred.

Examples of the azo reagents include diethylazodicarboxylic acid (DEAD),1,1′-azobis(N,N-dimethylformamide) (TMAD),1,1′-(azodicarbonyl)dipiperidine (ADDP),1,1′-azobis(N,N-diisopropylformamide) (TIPA), and1,6-dimethyl-1,5,7-hexahydro-1,4,6,7-tetrazocine-2,5-dione (DHTD). Ofthese, diethylazodicarboxylic acid is particularly preferred.

Examples of the reaction solvents which may be used includedimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane,acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, andmethylene chloride. Of these, dimethylformamide, tetrahydrofuran,dioxane, acetonitrile are preferred, with dimethylformamide andtetrahydrofuran being particularly preferred.

<Method B>

Method B can be carried out by dissolving the compound (2), a thiolderivative (4), and a phosphonium ylide reagent in a reaction solventand leading to the reaction under argon or nitrogen atmosphere for 2hours to 12 hours at room temperature to 120° C., preferably at 80° C.to 100° C.

Examples of the phosphonium ylide reagents which may be used in thereaction include alkanoylmethylenetrialkylphosphorane,alkanoylmethylenetriarylphosphorane,alkoxycarbonylmethylenetrialkylphosphorane,alkoxycarbonylmethylenetriarylphosphorane,cyanomethylenetrialkylphosphorane, and cyanomethylenetriarylphosphorane.Examples of the trialkyl include trimethyl, triethyl, tripropyl,triisopropyl, tributyl, triisobutyl, and tricyclohexyl, and examples ofthe triaryl include triphenyl and diphenylpolystyrene.

Alternatively, the above method may be carried out using a phosphoniumhalide reagent instead of the phosphonium yilde reagent, to be reactedto the compound (2) and the thiol derivative (4) in the presence of abase.

Examples of the phosphonium halide reagents used in the above caseinclude (cyanomethyl)trialkylphosphonium halide,(cyanomethyl)triarylphosphonium halide,(alkylcarbonylmethyl)trialkylphosphonium halide,(alkylcarbonylmethyl)triarylphosphonium halide,(alkoxycarbonylmethyl)trialkylphosphonium halide, and(alkoxycarbonylmethyl)triarylphosphonium halide.

Among the above phosphonium halide reagents, each of(cyanomethyl)trialkylphosphonium halide and(cyanomethyl)triarylphosphonium halide may be prepared by reacting thecorresponding halogenated acetonitrile with the correspondingtrialkylphosphine or triarylphosphine (Tetrahedron, Vol. 57, p.5451–5454, 2001). Similarly, each of the other phosphonium halidereagents may be prepared by reacting the correspondingalkanoylhalomethyl or alkoxycarbonylhalomethyl with the correspondingtrialkylphosphine or triarylphosphine.

Examples of the trialkylphosphines and triarylphosphines used in theabove case include those mentioned in relation to Method A. Among them,trimethylphosphine, tributylphosphine, and triphenylphosphine arepreferred, with trimethylphosphine being particularly preferred.

Examples of the above alkanoyl include formyl, acetyl, propionyl, andbutyryl, with acetyl and propionyl being preferred. Examples of thealkoxy in alkoxycarbonyl include methoxy, ethoxy, propoxy, and butoxy,with methoxy, ethoxy, and butoxy being preferred.

Preferred halogen atoms are a chlorine atom, a bromine atom, and aniodine atom.

Examples of the bases include organic bases such as triethylamine,N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and1,5-diazabicyclo[4.3.0]non-5-ene (DBN); and inorganic bases such aspotassium carbonate, sodium carbonate, cesium carbonate, lithiumcarbonate, lithium diisopropylamide, and potassium hexamethyldisilazide.Of these, N,N-diisopropylethylamine, potassium carbonate, lithiumdiisopropylamide, and potassium hexamethyldisilazide are preferred, withN,N-diisopropylethylamine and potassium carbonate being particularlypreferred.

Examples of preferred reaction solvents include dioxane,tetrahydrofuran, toluene, benzene, dimethylformamide, dimethylsulfoxide,acetonitrile, and propionitrile of these, propionitrile is particularlypreferred.

<Method C>

Method C can be carried out by dissolving the compound (2), a thiolderivative (4′), and a phosphine reagent in the same reaction solvent asemployed in Method A and leading to the reaction under argon or nitrogenatmosphere for 2 hours to 2 days at room temperature to 100° C.,preferably at 60° C. to 100° C.

In the reaction, the same trialkylphosphines and triarylphosphines asmentioned in relation to Method A are employed the phosphine reagent.Specific examples include trimethylphosphine, triethylphosphine,tripropylphosphine, triisopropylphosphine, tributylphosphine,triisobutylphosphine, tricyclohexylphosphine, triphenylphosphine,diphenylphosphinopolystyrene. Of these, trimethylphosphine,tributylphosphine, and triphenylphosphine are preferred, withtrimethylphosphine and triphenylphosphine being particularly preferred.

Notably, the thiol derivatives (4) and (4′) can be produced through theaforementioned method disclosed in PCT Patent Publication WO 98/54153pamphlet or a similar method.

The compound (1) can be produced through, for example, thebelow-described Step-A and Step-B.

[Step-A]

3-Amino-2,4-dihalogeno-6-methylpyridine (7) is acylated in a solvent byuse of an acid halide (7) in the presence of a base, to thereby producean acetamide compound (6).

Examples of the base include organic bases such as pyridine,triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine,N,N-dimethylaniline, and N,N-diethylaniline; inorganic bases such asalkali metal hydrogencarbonates (e.g., potassium hydrogencarbonate andsodium hydrogencarbonate) and alkali metal carbonates (e.g., potassiumcarbonate and sodium carbonate).

Examples of the solvents which are preferably employed include methylenechloride, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran,ethyl acetate, benzene, and toluene. The reaction is preferablyperformed for 0.5 to one day at 0 to 80° C., more preferably 0° C. toroom temperature.

[Step-B]

To a solution of the acetamide compound (6), a1-(hydroxyalkyl)piperazine (a) is added in the presence or absence of abase, so as to alkylate the amino group of the piperazine (a), wherebythe hydroxyalkyl cyclic diamine compound (1) can be produced.

Examples of the bases which can be used include inorganic bases such asalkali metal carbonates (e.g., potassium carbonate and sodium carbonate)and alkali metal hydrogencarbonates (e.g., potassium hydrogencarbonateand sodium hydrogencarbonate); and organic bases such as pyridine,triethylamine, N,N-diisopropylethylamine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), and N,N-dimethylaniline.

As a solvent, acetonitrile, acetone, tetrahydrofuran,N,N-dimethylformamide, etc. may be employed. Alternatively, the aboveoraganic solvent containing water can also be used in accordance withneeds. Among these solvents, acetonitrile is particularly preferred.

Preferably, the reaction is performed for 0.5 hours to one day at 0 to80° C., more preferably 0° C. to room temperature.

Notably, both the compound (7) in which R¹ is a bromine atom; i.e.,3-amino-2,4-dibromo-6-methylpyridine (7a), and the acetamide compound(6) are novel compounds, which have never been disclosed in anyliterature.

3-Amino-2,4-dibromo-6-methylpyridine (7a) may be produced from, forexample, 2,4-dihydroxy-6-methyl-3-nitropyridine (23) through thefollowing reaction steps. The resultant2,4-dibromo-6-methyl-3-nitropyridine (24) is also a novel compound.

The compound (23); i.e., a dihydroxy species (23), may be brominated byuse of a bromination agent in the presence or absence of a base, in asolvent or under solvent-free conditions. Examples of the brominationagents include phosphorus trioxide, phosphorus oxybromide, phosphoruspentabromide, and phosphorus oxybromide-phosphorus pentabromide. Ofthese, phosphorus oxybromide is preferred. Examples of the bases includeN,N-diethylaniline. Examples of the solvents includeN,N-dimethylformaldehyde, benzene, chlorobenzene, 1,2-dichloroethane,and dimethyl sulfoxide. The reaction is preferably performed for one to10 hours at 50 to 150° C., more preferably 100 to 130° C.

The nitro group of the compound (24) can be reduced through, forexample, the following methods: reduction by use of a metallic catalystin the presence of a hydrogen source such as hydrogen gas (Method A);reduction by use of a metal such as zinc (Method B); and reduction byuse of a reducing agent such as sodium hydrosulfite (Na₂S₂O₄) (MethodC).

According to Method A, the nitro group can be reduced in an appropriatesolvent in the presence of a hydrogen source such as hydrogen gas,cyclohexadiene, or formic acid and a metallic reduction catalyst such asplatinum, palladium, or Raney nickel. Examples of the solvents includealcoholic solvents such as methanol, ethanol, and isopropyl alcohol;solvents such as ethyl acetate, tetrahydrofuran, acetic acid,N,N-dimethylformamide, dioxane, and mixtures thereof; and the aboveorganic solvent containing water. The reaction is preferably performedfor 0.5 hours to one day at 0 to 100° C., more preferably roomtemperature to 80° C.

According to Method B, the nitro group can be reduced in a solvent inthe presence of a metallic component such as zinc, iron, tin, or tin(II)chloride. Examples of the solvents include alcoholic solvents such asethanol and isopropyl alcohol; acetic acid; and the above organicsolvent containing water. An acid such as hydrochloric acid or sulfuricacid may also be added in accordance with needs. The reaction ispreferably performed for 0.5 hours to one day at 0 to 100° C.

According to Method C, the nitro group can be reduced in a solventthrough addition of a sulfur-containing reducing agent such as sodiumhydrosulfite, sodium hydrogensulfide, sodium sulfide, or hydrogensulfide. Of these, sodium hydrosulfite is particularly preferred.Examples of preferred solvents include alcoholic solvents such asmethanol, ethanol, and isopropyl alcohol; and aqueous solventscontaining tetrahydrofuran, dioxane, or a similar compound. In thereduction, an amine additive such as ammonia, ethylenediamine orpropanediamine may be added. The reaction is preferably performed for0.5 to one day at room temperature to 100° C., more preferably roomtemperature to 80° C.

EXAMPLES

The present invention will next be described in more detail by way ofexamples.

Example 1 Synthesis of 2,4-dibromo-6-methyl-3-nitropyridine

In a nitrogen atmosphere, phosphorus oxybromide (58.0 g, 202 mmol) wasmelted with heat at 65° C., and 2,4-dihydroxy-6-methyl-3-nitropyridine(6.00 g, 35.3 mmol) was added to the melt with stirring. The mixture washeated to 120° C. and stirred for 1 hour. The mixture was allowed tocool and water (100 mL) was added to the mixture, to thereby deactivateexcessive phosphorus oxybromide present in the mixture. The mixture wasextracted with chloroform. The organic layer was washed with saturatedbrine, followed by drying over sodium sulfate anhydrate andconcentrating under reduced pressure. The residue was purified throughsilica gel column chromatography (chloroform), to thereby yield 10.29 gof 2,4-dibromo-6-methyl-3-nitropyridine as pale yellow crystals (yield:98.6%). The product was recrystallized from diethyl ether-hexane, tothereby yield colorless crystals.

m.p.: 118–120° C.

IR (KBr) cm⁻¹: 1560, 1541, 1439, 1356, 1331.

¹H-NMR (CDCl₃)δ: 2.61 (3H, s), 7.46(1H, s).

Elementary analysis: as formula C₆H₄Br₂N₂O₂ Calculated: C,24.35; H,1.36; N, 9.47; Br, 54.00 Found: C,24.29; H, 1.41; N, 9.44; Br, 54.18

Example 2 Synthesis of 3-amino-2,4-dibromo-6-methylpyridine

2,4-Dibromo-6-methyl-3-nitropyridine (1.0 g, 3.38 mmol) was dissolved ina mixture of methanol (4 mL) and tetrahydrofuran (6 mL), and a solutionof sodium hydrosulfite (3.0 g, 17.23 mmol) in water (7 mL) was addedthereto over 5 minutes with stirring at 65° C. Subsequently, the mixturewas stirred for 30 minutes at 65° C. To the mixture, a solution ofsodium hydrosulfite (3.0 g, 17.23 mmol) in water (7 mL) was furtheradded over 5 minutes, and the mixture was stirred for 30 minutes at 65°C. The resultant mixture was allowed to cool, diluted with water, andthen the mixture was extracted with chloroform. The organic layer waswashed with saturated brine, followed by drying over sodium sulfateanhydrate and concentrating under reduced pressure, to thereby yield0.89 g of 3-amino-2,4-dibromo-6-methylpyridine as a colorless solid(yield 99%). The product was crystallized from hexane, to thereby obtaincolorless crystals.

m.p.: 93–94° C.

IR(KBr)cm⁻¹: 3413, 3308, 1609, 1567, 1533.

¹H-NMR(CDCl₃)δ: 2.41 (3H, s), 4.40 (2H, br.s), 7.18(1H, s).

Elementary analysis: as formula C₆H₆Br₂N₂ Calculated: C,27.10; H, 2.27;N, 10.53; Br, 60.09 Found: C,26.87; H, 2.27; N, 10.51; Br, 59.90

Example 3 Synthesis ofN-[2,4-dibromo-6-methylpyridin-3-yl]-2-bromoacetamide

3-Amino-2,4-dibromo-6-methylpyridine (1.16 g, 4.38 mmol) was dissolvedin methylene chloride (10 mL). N,N-dimethylaniline (0.77 g, 6.35 mmol)was added to the solution and then a solution of bromoacetyl bromide(1.03 g, 5.12 mmol) in dichloromethane (2 mL) was added dropwise theretoover 5 minutes with stirring and cooling with ice. After completion ofaddition, the temperature of the mixture was elevated to roomtemperature and stirred for 12 hours. The resultant mixture was washedsequentially with water, an aqueous saturated sodium hydrogencarbonatesolution, and saturated brine. Subsequently, the mixture was dried oversodium sulfate anhydrate and concentrated under reduced pressure. Theresidue was crystallized from hexane-acetone, to thereby yield 1.44 g ofN-[2,4-dibromo-6-methylpyridin-3-yl]-2-bromoacetamide as colorlesscrystals (yield 85.3%).

m.p.: 197–199° C.

IR(KBr)cm⁻¹: 3437, 3195, 1672, 1574, 1546.

¹H-NMR(CDCl₃)δ: 2.54 (3H, s), 4.09 (2H, s), 7.43 (1H, s), 7.91(1H,br.s).

Elementary analysis: as formula C8H₇Br₃N₂O Calculated: C,24.84; H, 1.82;N, 7.24; Br, 61.96 Found: C,24.86; H, 1.83; N, 7.34; Br, 62.01

Example 4 Synthesis ofN-[2,4-dibromo-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide

N-[2,4-Dibromo-6-methylpyridin-3-yl]-2-bromoacetamide (1.4 g, 37.3 mmol)was dissolved in acetonitrile (60 mL). 1-(2-Hydroxyethyl)piperazine(0.58 g, 4.48 mmol) was added to the solution with stirring and coolingwith ice, and then potassium carbonate (37.5 g, 0.271 mol) was addedthereto. The temperature of the mixture was elevated to roomtemperature, and the mixture was stirred for 24 hours. After completionof reaction, the solvent was removed under reduced pressure. Chloroformand water was added to the residue, and the organic layer was collectedfrom the mixture. The aqueous layer was further extracted withchloroform and the two organic layers were combined together. Thecombined organic layer was washed with saturated brine, dried oversodium sulfate anhydrate, and concentrated under reduced pressure. Theresidue was purified through silica gel column chromatography(developer: ammonia-saturated methanol/chloroform=1/20), to therebyobtain 1.613 g ofN-[2,4-dibromo-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamideas an amorphous (yield: 99%).

IR(film)cm⁻¹: 3290, 1695, 1607, 1572, 1481.

¹H-NMR(CDCl₃)δ: 2.53 (3H, s), 2.59 (2H, t, J=5.6 Hz), 2.60–2.70 (4H, m),2.72–2.85 (4H, m), 3.22 (2H, s), 3.64 (2H, t, J=5.6 Hz), 7.42 (1H, s),8.96 (1H, br.s).

EIMS m/z (relative intensity): 100(100), 434(Br, Br), 436(Br, ⁸¹Br),438(⁸¹Br, ⁸¹Br).

HRMS(C₁₄H₂₀N₄O₂Br) Calculated: 433.9952, 435.9932, 437.9912. Found:433.9948, 435.9949, 437.9929.

Example 5 Synthesis ofN-[2,4-dichloro-6-methylpyridin-3-yl]-2-bromoacetamide

The procedure of Example 3 was repeated, except that3-amino-2,6-dichloro-6-methylpyridine was used instead of3-amino-2,4-dibromo-6-methylpyridine, to thereby yieldN-[2,4-dichloro-6-methylpyridin-3-yl]-2-bromoacetamide.

m.p. 184–185° C.

IR(KBr)cm⁻¹: 3227, 3018, 1672, 1581, 1557, 1519, 1452.

¹H-NMR (DMSO-d₆)δ: 2.53 (3H, s), 4.13 (2H, s), 7.64 (1H, s), 10.40 (1H,br.s)

Elementary analysis: formula as C₈H₇BrCl₂N₂O

Calculated: C, 32.25; H, 2.37; N, 9.40. Found: C, 32.30; H, 2.38; N,9.36.

Example 6 Synthesis ofN-[2,4-dichloro-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide

The procedure of Example 4 was repeated, except thatN-[2,4-dichloro-6-methylpyridin-3-yl]-2-bromoacetamide was used insteadof N-[2,4-dibromo-6-methylpyridin-3-yl]-2-bromoacetamide, to therebyyieldN-[2,4-dichloro-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide.

m.p.: 110–111° C.

IR (KBr)cm⁻¹: 3304, 3248, 2939, 2824, 1691, 1674, 1581, 1541.

¹H-NMR (CDCl₃)δ: 2.53 (3H, s), 2.60 (2H, t, J=5.3 Hz), 2.59–2.83 (8H,m), 3.23 (2H, s), 3.64 (2H, t, J=5.3 Hz), 7.24 (1H, s), 8.93 (1H, br.s).

Elementary analysis: formula as C₁₄H₂₀Cl₂N₄O₂.0.1H₂O

Calculated: C, 48.17; H, 5.83; N, 16.05; Cl, 20.31. Found: C, 48.02; H,5.89; N, 16.08; Cl; 20.28.

Example 7 Synthesis of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide

A solution of sodium thiomethoxide (7.0 g, 100 mmol) in dimethylsulfoxide (100 mL) was added to a solution ofN-[2,4-dichloro-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide(7.0 g, 20 mmol) and 18-crown-6 (530 mg, 2 mmol) in dimethyl sulfoxide(14 mL). The resulting mixture was stirred for 1 hour at 100° C. Thereaction mixture was allowed to cool, and then chloroform and water wereadded thereto. The organic layer was collected from the mixture, and theaqueous layer was further extracted with chloroform. The organic layerswere combined together, and the combined organic layer was washedsequentially with water and saturated brine, followed by drying oversodium sulfate anhydrate. The solvent was removed therefrom. The aqueouslayer which had been employed for washing was extracted with chloroform,and the obtained organic layer was washed sequentially with water andsaturated brine. Subsequently, the solution was dried over sodiumsulfate anhydrate, and the solvent was removed. The combined residue waspurified through silica gel column chromatography (developer:chloroform/ammonia-saturated methanol=20/1), to thereby yield 6.68 g of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamideas colorless crystals (yield: 90.1%). The product was recrystallizedfrom ethanol-diethyl ether, to thereby yield the product as colorlessneedles.

m.p.: 119–120° C.

IR (neat): 3335, 2924, 2827, 1688, 1478.

¹H-NMR (CDCl₃)δ: 2.42 (3H, s), 2.50 (3H, s), 2.52 (3H, s), 2.58 (2H, t,J=5.3 Hz), 2.59–2.88 (8H, m), 3.21 (2H, s), 3.64 (2H, t, J=5.3 Hz), 6.70(1H, s), 8.54 (1H, br s).

EIMS m/z (relative intensity): 370 (M⁺), 143 (100).

Elementary analysis: formula as C₁₆H₂₆N₄O₂S₂

Calculated: C, 51.86; H, 7.07; N, 15.12; S; 17.31. Found: C, 51.84; H,7.00; N, 14.92; S; 17.34.

Example 8 Synthesis of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide

In Example 8,N-[2,4-dibromo-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide(10.0 g, 23 mmol) was used instead ofN-[2,4-dichloro-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamideused in Example 7. In a manner similar to that of Example 7, theresulting mixture was stirred for 3 hours at 70° C., followed bypost-treatment, to thereby yield 7.79 g of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamideas colorless crystals (yield: 91.8%).

Example 9 Synthesis of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide

A 15% (w/v) aqueous solution (269 mL) of sodium thiomethoxide (576 mmol)was added to a solution ofN-[2,4-dichloro-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide(10.0 g, 29 mmol) and 18-crown-6 (1.52 g, 5.8 mmol) in dimethylsulfoxide (200 mL). The resulting mixture was stirred for 5 hours at100° C. and further stirred for 1 hour at 110° C. The reaction mixturewas allowed to cool, and chloroform and water were added thereto. Theorganic layer was collected, and the aqueous layer was further extractedwith chloroform. The combined organic layer was washed sequentially withwater and saturated brine, followed by drying over sodium sulfateanhydrate. The solvent was removed therefrom. The aqueous layer whichhad been employed for washing was extracted with chloroform, and theorganic layer was washed sequentially with water and saturated brine.Subsequently, the solution was dried over sodium sulfate anhydrate, andthe solvent was removed. The combined residue was purified throughsilica gel column chromatography (developer:chloroform/ammonia-saturated methanol=20/1), to thereby yield 6.63 g of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamideas colorless crystals (yield: 62.1%).

Example 10 Synthesis of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide

In Example 10,N-[2,4-dibromo-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamidewas used instead ofN-[2,4-dichloro-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamideused in Example 9. In a manner similar to that of Example 9, theresulting mixture was stirred for 2 hours at 100° C., followed bypost-treatment, to thereby yield 6.60 g of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamideas colorless crystals (yield: 77.7%).

Example 11 Synthesis of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide

Morpholine (9.0 mL) was added toN-(2,4-dichloro-6-methylpyridin-3-yl)-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide(1.0 g, 2.88 mmol), and the mixture was stirred for 24 hours at 100° C.The reaction mixture was allowed to cool and concentrated under reducedpressure. The residue was purified through silica gel columnchromatography (developer: chloroform/ammonia-saturated methanol=50/1),to thereby yield 826 mg of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamidein a yellow amorphous state (yield: 63.9%).

¹H-NMR (CDCl₃)δ: 2.41 (3H, s), 2.50–2.80 (10H, m), 3.00 (4H, t, J=4.5Hz), 3.12 (4H, t, J=4.5 Hz), 3.18 (2H, s), 3.55–3.80 (10H, m), 6.50 (1H,s), 8.52 (1H, br. s)

Example 12 Synthesis of2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide

2-[4-(2-Hydroxyethyl)piperazin-l-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide(104.94 g, 0.286 mol) was dissolved in tetrahydrofuran (1.4 L), andtriethylamine (48.5 g, 0.479 mol), 4-dimethylaminopyridine (1.76 g, 14.4mmol), and methanesulfonyl chloride (42 g, 0.366 mol) were sequentiallyadded to the solution under cooling with ice, followed by stirring for 1hour at the same temperature. The reaction mixture was filtrated, andthe filtrate was concentrated under reduced pressure, to thereby yield144.92 g of a pale yellow foamed substance. The product was dissolved inN,N-dimethylformamide (1 L), and 2-mercaptobenzimidazole (48.58 g, 0.323mol), potassium carbonate (48.58 g, 0.351 mol), and 18-crown-6 (3.56 g,13.5 mmol) were added to the resultant solution at room temperature,followed by stirring for 3 hours at 80° C. The reaction mixture wasconcentrated under reduced pressure, and the residue was partitioned byadding chloroform and water. The aqueous layer was extracted withchloroform. The combined organic layer was washed with saturated brine,dried over sodium sulfate anhydrate, and concentrated under reducedpressure. The residue was purified through silica gel columnchromatography (developer: hexane/acetone=1/1–1/3), to thereby yield55.85 g of2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide(yield: 39.2%).

Example 13 Synthesis of2-[4-[2-(7-trifluoromethylbenzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-mercaptobenzimidazole was replaced by2-mercapto-7-trifluoromethylbenzoxazole, to thereby yield the titlecompound as colorless needles.

m.p.: 155–156° C. (decomposition)

Example 14 Synthesis of2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-mercaptobenzimidazole was replaced by 2-mercaptobenzoxazole, tothereby yield the title compound as colorless needles.

m.p.: 140–142° C.

Example 15 Synthesis of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide

Sodium hydride (1.26 g) was added to 2,2,2-trifluoroethanol (12 mL)under cooling with ice, and the mixture was stirred for 10 minutes atthe same temperature. A solution ofN-[2,4-dichloro-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide(2.00 g, 5.76 mmol) in dimethyl sulfoxide (80 mL) was added to thereaction mixture, and the resultant mixture was stirred for 24 hours at100° C. The reaction mixture was allowed to cool, and ethyl acetate andwater were added to the mixture. The organic layer was separated, andthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were washed sequentially with water and saturated brine, anddried over sodium sulfate anhydrate. The solvent was removed underreduced pressure, and the residue was purified through silica gel columnchromatography (developer: chloroform/ammonia-saturated methanol=200/3),to thereby yield 2.35 g of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide(yield: 86.0%) as yellow crystals.

¹H-NMR (CDCl₃)δ: 2.42 (3H, s), 2.48–2.82 (10H, m), 3.17 (2H, s), 3.63(2H, t, J=5.4 Hz), 4.41 (2H, q, J=8.0 Hz), 4.75 (2H, q, J=8.5 Hz), 6.47(1H, s), 8.38 (1H, br. s).

Example 16 Synthesis of2-[4-[2-(5,6-difluorobenzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide,and 2-mercaptobenzimidazole was replaced by5,6-difluoro-2-mercaptobenzimidazole, to thereby yield the titlecompound as a colorless foamed substance.

¹H-NMR (CDCl₃)δ: 2.42 (3H, s), 2.50–3.05 (10H, m), 3.25 (2H, t, J=5.3Hz), 3.31 (2H, s), 4.42 (2H, q, J=8.0 Hz), 4.75 (2H, q, J=8.5 Hz), 6.46(1H, s), 7.12 (1H, br. s), 7.41 (1H, br. s), 8.26 (1H, s), 13.20 (1H,br. s).

Example 17 Synthesis of2-[4-[2-(5-fluorobenzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide,and 2-mercaptobenzimidazole was replaced by5-fluoro-2-mercaptobenzimidazole, to thereby yield the title compound asa pale brown foamed substance.

¹H-NMR (CDCl₃)δ: 2.41 (3H, s), 2.66–2.91 (8H, m), 2.97 (2H, t, J=5.1Hz), 3.25 (2H, t, J=5.1 Hz), 3.29 (2H, s), 4.41 (2H, q, J=8.0 Hz), 4.75(2H, q, J=8.5 Hz), 6.45 (1H, s), 6.93 (1H, td, J=9.0, 2.3 Hz), 7.10–7.56(2H, m), 8.28 (1H, s), 13.14 (1H, br. s)

Example 18 Synthesis of2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide,and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzoxazole, tothereby yield the title compound as a colorless crystalline powder.

¹H-NMR (CDCl₃)δ: 2.42 (3H, s), 2.54–2.76 (8H, m), 2.84 (2H, t, J=6.9Hz), 3.15 (2H, s), 3.49 (2H, t, J=6.9 Hz), 4.41 (2H, q, J=8.0 Hz), 4.75(2H, q, J=8.5 Hz), 6.46 (1H, s), 7.25–7.35 (2H, m), 7.43 (1H, d, J=7.8Hz), 7.59 (1H, d, J=7.8 Hz), 8.38 (1H, s).

Example 19 Synthesis of2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide,to thereby yield the title compound as a colorless crystalline powder.

¹H-NMR (CDCl₃)δ: 2.43 (3H, s), 2.65–2.97 (8H, m), 3.01 (2H, t, J=5.0Hz), 3.23 (2H, t, J=5.0 Hz), 3.31 (2H, s), 4.42 (2H, q, J=8.0 Hz), 4.75(2H, q, J=8.5 Hz), 6.48 (1H, s), 7.6–7.24 (2H, m), 7.41–7.65 (2H, m),8.26 (1H, s)

Example 20 Synthesis of2-[4-[2-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide,and 2-mercaptobenzimidazole was replaced by5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole, to thereby yieldthe title compound as a colorless crystalline powder.

¹H-NMR (CDCl₃)δ: 1.32 (6H, d, J=6.9 Hz), 2.42 (3H, s), 2.52 (3H, s),2.56–2.78 (8H, m), 2.85 (2H, t, J=7.0 Hz), 3.15 (2H, s), 3.22 (1H, sept,J=6.9 Hz), 3.48 (2H, t, J=7.0 Hz), 4.41 (2H, q, J=8.0 Hz), 4.74 (2H, q,J=8.5 Hz), 6.46 (1H, s), 7.07 (1H, s), 8.37 (1H, s).

Example 21 Synthesis of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-dimethoxy-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 7 were repeated, except thatsodium thiomethoxide was replaced by sodium methoxide, to thereby yieldthe title compound as a colorless crystalline powder.

¹H-NMR (CDCl₃)δ: 2.42 (3H, s), 2.48–2.83 (10H, m), 3.17 (2H, s), 3,64(2H, t, J=5.3 Hz), 3.83 (3H, s), 3.91 (3H, s), 6.43 (1H, s), 8.26 (1H,br. s).

Example 22 Synthesis of2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-dimethoxy-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-dimethoxy-6-methylpyridin-3-yl]acetamide,and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzoxazole, tothereby yield the title compound as a colorless crystalline powder.

¹H-NMR (CDCl₃)δ: 2.42 (3H, s), 2.54–2.76 (8H, m), 2.84 (2H, t, J=7.0Hz), 3.16 (2H, s), 3.49 (2H, t, J=7.0 Hz), 3.83 (3H, s), 3.91 (3H, s),6.42 (1H, s), 7.20–7.31 (2H, m), 7.41–7.46 (1H, m), 7.56–7.61 (1H, m),8.25 (1H, br. s).

Example 23 Synthesis of2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(1-methylethoxy)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 7 were repeated, except thatsodium thiomethoxide was replaced by sodium isopropoxide, to therebyyield2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(1-methylethoxy)-6-methylpyridin-3-yl]acetamideas a colorless crystalline powder.

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(1-methylethoxy)-6-methylpyridin-3-yl]acetamide,to thereby yield the title compound as a colorless foamed substance.

¹H-NMR (CDCl₃)δ: 1.28 (6H, d, J=6.3 Hz), 1.32 (6H, d, J =6.1 Hz), 2.38(3H, s), 2.58–3.22 (10H, m), 3.23 (2H, t, J =5.0 Hz), 3.29 (2H, s), 4.58(1H, sept, J=6.1 Hz), 5.34 (1H, sept, J=6.3 Hz), 6.35 (1H, s), 7.18–7.22(2H, m), 7.30–7.75 (2H, m), 7.99 (1H, br. s).

Example 24 Synthesis of2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(1-methylethoxy)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(1-methylethoxy)-6-methylpyridin-3-yl]acetamideand 2-mercaptobenzimidazole was replaced by 2-mercaptobenzoxazole, tothereby yield the title compound as a pale yellow viscous oil.

¹H-NMR (CDCl₃)δ: 1.28 (6H, d, J=6.1 Hz), 1.32 (6h, J=6.1 Hz), 2.37 (3H,s), 2.49–2.78 (8H, m), 2.84 (2H, t, J=7.0 Hz), 3.13 (2H, s), 3.49 (2H,t, J=7.0 Hz), 4.58 (1H, sept, J=6.1 Hz), 5.33 (1H, sept, J=6.1 Hz), 6.34(1H, s), 7.17–7.31 (2H, m), 7.43 (1H, d, J=6.8 Hz), 7.58 (1H, d, J=7.3Hz), 8.11 (1H, br. s).

Example 25 Synthesis of2-[4-[2-(oxazolo[4,5-b]pyridin-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(1-methylethoxy)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(1-methylethoxy)-6-methylpyridin-3-yl]acetamide,and 2-mercaptobenzimidazole was replaced by2-mercaptooxazolo[4,5-b]pyridine, to thereby yield the title compound asa yellow oil.

¹H-NMR (CDCl₃)δ: 1.28 (6H, d, J=6.2 Hz), 1.32 (6h, J=6.1 Hz), 2.37 (3H,s), 2.49–2.82 (8H, m), 2.87 (2H, t, J=6.9 Hz), 3.14 (2H, s), 3.56 (2H,t, J=6.9 Hz), 4.58 (1H, sept, J=6.1 Hz), 5.32 (1H, sept, J=6.2 Hz), 6.34(1H, s), 7.80 (2H, dd, J=8.0, 4.9 Hz), 7.69 (1H, dd, J=8.0, 1.5 Hz),8.11 (1H, br. s), 8.46 (1H, dd, J=4.9, 1.5 Hz).

Example 26 Synthesis of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methyl-3-pyridyl]acetamide

2-[4-(2-Hydroxyethyl)piperazin-1-yl]-N-[2,4-dibromo-6-methyl-3-pyridyl]acetamide(1.00 g, 2.29 mmol) was dissolved in pyrrolidine (10 mL), and thesolution was subjected to reflux for 4 days. The reaction mixture wasconcentrated under reduced pressure, and the residue was subjected toseparation through silica gel column chromatography (developer:hexane:acetone=2:1), to thereby yield a crude product of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methyl-3-pyridyl]acetamide(1.22 g) as a brown foamed substance. The crude product was dissolved inpyridine (20 mL), and acetic anhydride (10 mL) was added thereto undercooling with ice, followed by stirring for 14 hours at room temperature.The reaction mixture was concentrated under reduced pressure. Toluene(70 mL) was added to the residue and then evaporated three times,followed by purification through silica gel column chromatography(developer: chloroform:methanol=20:1→chloroform:ammonia-saturatedmethanol=50:1→chloroform:ammonia-saturated methanol=20:1), to therebyyield a brown oil (1.05 g). The oil was dissolved in ammonia-saturatedmethanol (30 mL), and the solution was stirred for 14 hours at roomtemperature. The reaction mixture was concentrated under reducedpressure, and the residue was purified through silica gel columnchromatography (developer: chloroform:ammonia-saturatedmethanol=100:1→chloroform:ammonia-saturated methanol=20:1), to therebyyield2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methyl-3-pyridyl]acetamide(911 mg, yield 95%) as a pale brown foamed susbtance.

¹H-NMR (CDCl₃)δ: 1.75–2.05 (8H, m), 2.31 (3H, s), 2.50–2.75 (10H, m),3.18 (2H, s), 3.25–3.55 (8H, m), 3.63 (2H, t, J=5.2 Hz), 6.04 (1H, s),8.36 (1H, br. s).

Example 27 Synthesis of2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methyl-3-pyridyl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide,to thereby yield the title compound as a pale yellow foamed substance.

¹H-NMR (DMSO-d₆, 120° C.)δ: 1.72–1.87 (8H, m), 2.19 (3H, s), 2.33–2.65(8H, m), 2.74 (2H, m), 3.05 (2H, br. s), 3.26–3.45 (10H, m), 5.99 (1H,s), 7.07–7.12 (2H, m), 7.37–7.45 (2H, m), 8.41 (1H, br.), 12.17 (1H,br.).

Example 28 Synthesis of2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methyl-3-pyridyl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide,and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzoxazole, tothereby yield the title compound as a pale yellow solid.

¹H-NMR (DMSO-d₆, 120° C.)δ: 1.71–1.88 (8H, m), 2.19 (3H, s), 2.43–2.64(8H, m), 2.78 (2H, m), 3.03 (2H, br. s), 3.26–3.42 (8H, m), 3.47 (2H,m), 5.99 (1H, s), 7.26–7.34 (2H, m), 7.54–7.61 (2H, m), 8.40 (1H, br.).

Example 29 Synthesis of2-[4-[2-(oxazolo[4,5-b]pyridin-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide:

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide,and 2-mercaptobenzimidazole was replaced by2-mercaptooxazolo[4,5-b]pyridine, to thereby yield the title compound asa pale yellow oil.

¹H-NMR (DMSO-d₆, 120° C.)δ: 1.72–1.87 (8H, m), 2.19 (3H, s), 2.43–2.64(8H, m), 2.81 (2H, m), 3.03 (2H, br. s), 3.26–3.44 (8H, m), 3.53 (2H,m), 5.99 (1H, s), 7.30 (1H, m), 7.96 (1H, m), 8.36–8.44 (2H, m).

Example 30 Synthesis of2-[4-[2-(7-trifluoromethylbenzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide,and 2-mercaptobenzimidazole was replaced by2-mercapto-7-trifluoromethylbenzoxazole, to thereby yield the titlecompound as a pale yellow oil.

¹H-NMR (DMSO-d₆, 120° C.)δ: 1.72–1.90 (8H, m), 2.19 (3H, s), 2.43–2.61(8H, m), 2.80 (2H, m), 3.02 (2H, br. s), 3.26–3.45 (8H, m), 3.51 (2H,m), 6.00 (1H, s), 7.51 (1H, t, J=7.8 Hz), 7.60 (1H, d, J=7.8 Hz), 7.89(1H, d, J=7.8 Hz), 8.41 (1H, br.).

Example 31 Synthesis of2-[4-[2-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methyl-3-pyridyl]acetamide,and 2-mercaptobenzimidazole was replaced by2-mercapto-5-chloro-7-isopropyl-4-methylbenzoxazole, to thereby yieldthe title compound as a pale yellow oil.

¹H-NMR (DMSO-d₆, 120° C.)δ: 1.33 (6H, d, J=6.8 Hz), 1.72–1.90 (8H, m),2.21 (3H, s), 2.44–2.64 (8H, m), 2.80 (2H, m), 3.05 (2H, br. s), 3.23(1H, sept, J=6.8 Hz), 3.27–3.46 (8H, m), 3.48 (2H, m), 6.02 (1H, s),7.16 (1H, s), 8.46 (1H, br.)

Example 32 Synthesis of2-[4-[2-(benzothiazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methyl-3-pyridyl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide,and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzothiazole, tothereby yield the title compound as a pale yellow solid.

¹H-NMR (DMSO-d₆, 120° C.)δ: 1.71–1.88 (8H, m), 2.19 (3H, s), 2.44–2.63(8H, m), 2.78 (2H, m), 3.04 (2H, br. s), 3.26–3.44 (8H, m), 3.50 (2H,m), 5.99 (1H, s), 7.34 (1H, t, J=7.6 Hz), 7.45 (1H, t, J=7.6 Hz), 7.82(1H, d, J=7.6 Hz), 7.94 (1H, d, J=7.6 Hz,), 8.41 (1H, br.).

Example 33 Synthesis of2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide,to thereby yield the title compound as a colorless crystalline powder.

¹H-NMR (CDCl₃)δ: 2.42 (3H, s), 2.74–2.94 (8H, m), 2.95–3.06 (6H, m),3.07–3.21 (4H, m), 3.23–3.40 (4H, m), 3.68–3.88 (8H, m), 6.52 (1H, s),7.14–7.26 (2H, m), 7.44–7.63 (2H, m), 8.41 (1H, s).

Example 34 Synthesis of2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide,and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzoxazole, tothereby yield the title compound as a colorless foamed substance.

¹H-NMR (CDCl₃)δ: 2.41 (3H, s), 2.58–2.78 (8H, m), 2.86 (2H, t, J=6.9Hz), 2.94–3.04 (4H, m), 3.06–3.15 (4H, m), 3.16 (2H, s), 3.49 (2H, t,J=6.9 Hz), 3.68–3.82 (8H, m), 6.50 (1H, s), 7.20–7.32 (2H, m), 7.44 (1H,d, J=7.2 Hz), 7.59 (1H, d, J=7.2 Hz), 8.54 (1H, s).

Example 35 Synthesis of2-[4-[2-(oxazolo[4,5-b]pyridin-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide,and 2-mercaptobenzimidazole was replaced by2-mercaptooxazolo[4,5-b]pyridine, to thereby yield the title compound asa colorless foamed substance.

¹H-NMR (CDCl₃)δ: 2.41 (3H, s), 2.62–2.78 (8H, m), 2.89 (2H, t, J=6.7Hz), 3.01 (4H, t, J=4.6 Hz), 3.12 (4H, t, J=4.6 Hz), 3.17 (2H, s), 3.56(2H, t, J=6.7 Hz), 3.70–3.80 (8H, m), 6.50 (1H, s), 7.19 (1H, dd, J=8.0,5.0 Hz), 7.70 (1H, dd, J=8.0, 1.5 Hz), 8.46 (1H, dd, J=5.0, 1.5 Hz),8.53 (1H, s).

Example 36 Synthesis of2-[4-[2-(7-trifluoromethylbenzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide,and 2-mercaptobenzimidazole was replaced by2-mercapto-7-trifluoromethylbenzoxazole, to thereby yield the titlecompound as a colorless foamed substance.

¹H-NMR (CDCl₃)δ: 2.41 (3H, s), 2.58–2.77 (8H, m), 2.87 (2H, t, J=6.8Hz), 2.94–3.05 (4H, m), 3.06–3.19 (6H, m), 3.52 (2H, t, J=6.8 Hz),3.72–3.82 (8H, m), 6.50 (1H, s), 7.38 (1H, t, J=7.8 Hz), 7.48 (1H, d,J=7.8 Hz), 7.76 (1H, d, J=7.8 Hz), 8.53 (1H, s).

Example 37 Synthesis of2-[4-[2-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide,and 2-mercaptobenzimidazole was replaced by2-mercapto-5-chloro-7-isopropyl-4-methylbenzoxazole, to thereby yieldthe title compound as a colorless foamed substance.

¹H-NMR (CDCl₃)δ: 1.33 (6H, d, J=6.8 Hz), 2.41 (3H, s), 2.52 (3H, s),2.57–2.79 (8H, m), 2.87 (2H, t, J=6.9 Hz), 3.00 (4H, t, J=4.4 Hz), 3.12(4H, t, J=4.4 Hz), 3.16 (2H, s), 3.23 (1H, sept, J=6.8 Hz), 3.49 (2H, t,J=6.9 Hz), 3.66–3.84 (8H, m) 6.50 (1H, s), 7.08 (1H, s), 8.53 (1H, s).

Example 38 Synthesis of2-[4-[2-(benzothiazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide

The reaction and treatments of Example 12 were repeated, except that2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamidewas replaced by2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide,and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzothiazole, tothereby yield the title compound as a colorless foamed substance.

¹H-NMR (CDCl₃)δ: 2.40 (3H, s), 2.59–2.77 (8H, m), 2.86 (2H, t, J=7.0Hz), 3.00 (4H, t, J=4.5 Hz), 3.12 (4H, t, J=4.5 Hz), 3.16 (2H, m), 3.54(2H, t, J=7.0 Hz), 3.70–3.82 (8H, m), 6.50 (1H, s), 7.30 (1H, dt, J=7.7,1.1 Hz), 7.41 (1H, dt, J=7.7, 1.1 Hz), 7.76 (1H, d, J=7.7, Hz), 7.85(1H, d, J=7.7, Hz), 8.53 (1H, s).

Production Example 1 Synthesis of 3-amino-2,4-dichloro-6-methylpyridine

2,4-Dichloro-6-methyl-3-nitropyridine (30 g, 144.9 mmol) was dissolvedin ethanol (300 mL), and Raney nickel (1.50 g, 25.6 mmol) was added tothe solution, followed by stirring for 7 hours at 60° C. under hydrogenatmosphere (0.15 MPa). Raney nickel was removed through filtration, andthe filtrate was concentrated under reduced pressure. The residue wasdissolved in chloroform (60 mL), and the solution was left to stand forone hour. Subsequently, the formed insoluble substance was removedthrough filtration, and the filtrate was concentrated under reducedpressure, to thereby yield 24.62 g of3-amino-2,4-dichloro-6-methylpyridine (yield: 96%) as a colorless solid.The product was recrystallized from hexane, to thereby yield colorlesscrystals.

Example 39 Synthesis ofN-(2,4-dichloro-6-methylpyridin-3-yl)-2-bromoacetamide

3-Amino-2,4-dichloro-6-methylpyridine (48.0 g, 271.1 mmol) was dissolvedin chloroform (384 mL), and N,N-dimethylaniline (39.4 g, 325.1 mmol) wasadded to the solution. A solution of bromoacetyl bromide (65.7 g, 325.5mmol) in chloroform (96 mL) was added dropwise to the mixture understirring and under cooling with ice. The resultant mixture was stirredfor 1 hour at the same temperature and for 1 hour at room temperature.Subsequently, under cooling with ice, a solution of bromoacetyl bromide(27.4 g, 135.7 mmol) in chloroform (48 mL) was further added to theresultant mixture, followed by stirring for 1 hour at room temperature.Water (288 mL) was added to the reaction mixture, and the resultantmixture was stirred for 12 hours at room temperature. The reactionmixture was stirred for 2 hours under cooling with ice, and theprecipitated crystals were collected through filtration. The crystalswere washed with cold ethanol (96 mL) and dried at 50° C. by use of ablower, to thereby yield 58.81 g ofN-(2,4-dichloro-6-methylpyridin-3-yl)-2-bromoacetamide (yield: 73%) ascolorless crystals.

The above filtrate and the wash liquid were combined together, and theorganic layer was separated. The aqueous layer was extracted withchloroform (240 mL), and the resultant organic layer and theabove-separated organic layer were combined together. The combinedorganic layer was washed with saturated brine (240 mL) and dried oversodium sulfate anhydrate, followed by condensation under reducedpressure. The residue was dissolved in chloroform (48 mL) at 60° C., andthe solution was allowed to cool to room temperature, followed bystirring for 2 hours under cooling with ice. The precipitated crystalswere collected through filtration, washed with cold chloroform (24 mL),and dried at 50° C. by use of a blower, to thereby further yield 12.83 gof N-(2,4-dichloro-6-methylpyridin-3-yl)-2-bromoacetamide (yield: 16%)as colorless crystals.

Example 40 Synthesis ofN-(2,4-dichloro-6-methylpyridin-3-yl)-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide

N-(2,4-Dichloro-6-methylpyridin-3-yl)-2-bromoacetamide (70.0 g, 234.9mmol) was dissolved in acetonitrile (105 mL), and potassium carbonate(39.0 g, 282.2 mmol) was added to the solution under stirring and undercooling with ice. While the inner temperature was maintained at 5° C. orlower, a solution of 1-(2-hydroxyethyl)piperazine (36.7 g, 281.9 mmol)in acetonitrile (140 mL) was added dropwise to the resultant mixture.Thereafter, the temperature of the mixture was elevated to roomtemperature, and the mixture was stirred for 4 hours. The reactionmixture was extracted with chloroform-water, and the aqueous layer wasfurther extracted twice with chloroform. The combined organic layer waswashed with saturated brine and dried over sodium sulfate anhydrate,followed by condensation under reduced pressure. The residue wasrecrystallized from isopropanol and diisopropyl ether, to thereby yield73.57 g ofN-(2,4-dichloro-6-methylpyridin-3-yl)-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide(yield: 90%) as colorless crystals.

Example 41 Synthesis of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide

N-(2,4-Dichloro-6-methylpyridin-3-yl)-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide(58.0 g, 167.0 mmol) and 18-crown-6 (4.41 g, 16.7 mmol) were dissolvedin dimethyl sulfoxide (580 mL), and sodium thiomethoxide powder (46.8 g,667.7 mmol) was added to the solution under stirring and under coolingwith ice, followed by stirring for 2.5 hours at an inner temperature of65–75° C. The reaction mixture was allowed to cool to room temperature,and water was added to the mixture under cooling with ice, followed byextraction with chloroform. The aqueous layer was extracted withchloroform. The combined organic layer was washed with saturated brineand concentrated under reduced pressure. The residue was recrystallizedfrom isopropanol and diisopropyl ether, to thereby yield 43.83 g of2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide(yield: 71%) as colorless crystals.

Example 42 Synthesis of2-[4-(2-benzimidazol-2-ylthio)ethylpiperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide

2-[4-(2-Hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide(50.0 g, 134.9 mmol), 2-mercaptobenzimidazole (75.0 g, 499.3 mmol), andtriphenylphosphine (125.0 g, 476.6 mmol) were dried under reducedpressure and disolved in anhydrous N,N-dimethylformamide (500 mL). Asolution of diethyl azodicarboxylate (DEAD) in toluene (DEAD: 40% w/vtoluene solution, 168 mL, 385.9 mmol) was added dropwise to theresultant solution under stirring and under cooling with ice, and themixture was stirred for 2 hours at the same temperature. Subsequently,the temperature of the mixture was elevated to room temperature, and themixture was further stirred for 1 hour. The reaction mixture waspartitioned by adding chloroform (500 mL) and 1 mol/L hydrochloric acid(500 mL), and the aqueous layer was collected and washed twice withchloroform (500 mL). Acetonitrile (250 mL) was added to the aqueouslayer, and the aqueous layer was made basic by adding potassiumcarbonate, followed by stirring for 1 hour at room temperature. Theprecipitated crystals were collected through filtration, washedsequentially with water (300 mL) and acetonitrile (100 mL), and dried at60° C. by use of a blower, to thereby yield 65.38 g of2-[4-(2-benzimidazol-2-ylthio)ethylpiperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide(yield: 96.4%) as slightly yellowish white crystals.

1. A hydroxyalkyl cyclic diamine compound represented by the followingformula (1):

wherein R¹ denotes a halogen atom, m is 1 or 2, and n is an integer of 1to 6.